Racemic (dl or RS) 2,3-Dihyro-6-fluoro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione and 6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dion e have heretofore been reported [Sarges, U.S. Pat. No. 4,117,230] to be aldose reductase inhibitors, reflecting their value in controlling certain chronic complications arising from diabetes mellitus (e.g., diabetic cataracts and neuropathy.) Subsequently, in spite of the fact that R-, S- and RS-2,3-dihydro-6-fluoro-spiro-[4H-1-benzopyran-4-4'-imidazoline]-2',5'-dio ne are equipotent as anticonvulsant agents, it was determined that the aldose reductase activity resided in the S isomer (USAN: sorbinil; the dextrorotatory isomer having structure ##STR6## wherein X=F, Sarges U.S. Pat. No. 4,130,714), now a more highly potent aldose reductase inhibitor, reflecting its especial value in effectively controlling the chronic complications of diabetes mellitus.
Sorbinil was heretofore made by the resolution of the racemate, using highly toxic brucine as the resolving agent and wastefully producing an equal amount of the R-isomer which is virtually devoid of the desired activity. Unexpectedly, the resolution process for sorbinil does not provide an enabling disclosure for the synthesis of the corresponding S-6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-di one.
Also clinically useful in the treatment of diabetes mellitus are insulin and oral hypoglycemic agents such as sulfonylureas (e.g., chlorpropamide, tolbutamide, acetohexamide, tolazamide), biguanides (e.g. phenformin). A variety of other compounds which have been reported to have this type of activity, as recently reviewed by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y., (1979), pp. 1057-1080].